Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

• the present invention relates to new tetracyclic 1,4-oxygine compounds, a process for their preparation and pharmaceutical compositions containing them.
• n zero, 1 or 2;
• X represents:
• R represents:
• a (C 1 -C 10 )alkyl, (C 3 -C 10 )alkenyl or (C 3 -C 10 )alkynyl radical each in straight or branched chain and each optionally substituted by one or more cycloalkyl radicals having from 3 to 8 carbon atoms, or by an aryl radical selected from the radicals phenyl, thienyl and pyridyl, each of which is optionally substituted by one or more substituents selected from halogen atoms, the hydroxy radical, and alkyl and alkoxy radicals each having from 1 to 6 carbon atoms in straight or branched chain.
• the compounds of the invention have a trans ring junction between the 1,4-oxazine ring and the ring adjacent thereto.
• asymmetric carbon atoms implies that the compounds of the invention exist in the form of a racemic mixture and in the form of optical isomers, which are also included in the present invention.
• the compounds of formula I may form with pharmaceutically acceptable inorganic or organic acids physiologically tolerable acid addition salts, which also form part of the present invention.
• X' represents:
• D 2 dopaminergic receptor Those substances act on the D 2 dopaminergic receptor, to which they bind very strongly. As a result they can be used, when they are blockers of that D 2 receptor, in the treatment of schizophrenia and, when they are activators of that receptor, in the treatment of Parkinson's disease.
• D 2 receptor their strong activity in respect of the D 2 receptor means that their use brings about troublesome side effects, such as tardive dyskinesia, hyperprolactinaemia and amenorrhoea in the case of the blocking agents, and cardiovascular and motor effects in the case of the activators.
• D 3 receptor the concentration of which is very significant in the limbic system but very low in the nigrostriated nucleus and in the lactotrophic cells, encourages research into new medicaments that act on the dopaminergic system but that have as a preferential target the D 3 receptor and are thus exempt from the side effects typically associated with activity at the D 2 receptor as mentioned above.
• That selectivity makes the compounds of the present invention valuable especially for use as medicaments that act on the dopaminergic system without causing the undesirable effects of D 2 ligands.
• That activity of the compounds of the present invention has also been demonstrated in vivo by means of the reversal test of hypothermia induced by the prototype D 3 agonist (7-OH-DPAT) according to the method of M. J. Millan, Eur. J. Pharmacol. (1994), 260, R 3 -R 5 .
• the compounds of the present invention thus differ from the products of the prior art not only in their chemical structure but also in their pharmacological activity, which allows them to exert a beneficial effect when used in the treatment of Parkinson's disease J. Neur. Transm., (1993), 94, 11-19!, memory disorders Nature, (1990), 347, 146-151!, drag abuse Science, (1993), 260, 1814!, depression and psychoses.
• --A'--D--E-- represents: --(CH 2 ) 3 --, --(CH 2 ) 4 --, --S--(CH 2 ) 2 -- or --S--CH ⁇ CH--
• R' represents:
• a cycloalkyl radical having from 3 to 8 carbon atoms an aryl radical selected from the radicals phenyl, thienyl and pyridyl, each of which is optionally substituted by one or more substituents selected from halogen atoms, the hydroxy radical, and alkyl and alkoxy radicals each having from 1 to 6 carbon atoms in straight or branched chain, or
• a (C 1 -C 9 )alkyl, (C 2 -C 9 )alkenyl or (C 2 -C 9 )alkynyl radical each in straight or branched chain and each optionally substituted by one or more cycloalkyl radicals having from 3 to 8 carbon atoms, or by an aryl radical selected from the radicals phenyl, thienyl and pyridyl, each of which is optionally substituted by one or more substituents selected from halogen atoms, the hydroxy radical, and alkyl and alkoxy radicals each having from 1 to 6 carbon atoms in straight or branched chain,
• R" has the same meanings as R with the exception of hydrogen and methyl
• alkali metal hydride such as, for example, sodium hydride
• --A'--D--E-- represents --S--(CH 2 ) 2 -- or --S--CH ⁇ CH--
• --A"--D--E-- represents the group: ##STR21## wherein: p is as defined hereinbefore and m' represents 1 or 2;
• optically active forms of the compounds of formula I were obtained either from the optically active forms of the starting materials of formula II, or by splitting the racemic forms of the compounds of formula I, according to methods known from the literature.
• the starting materials of formula II are either known products or products obtained from known substances according to known methods as described hereinafter in Preparations 1 and 2.
• the present invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula I or a physiologically tolerable salt thereof, mixed with or associated with one or more appropriate pharmaceutical excipients.
• compositions so obtained are generally presented in dosage form containing from 0.5 to 25 mg of active ingredient. They may, for example, be in the form of tablets, dragees, gelatin capsules, suppositories or injectable or drinkable solutions and may be administered by the oral, rectal or parenteral mute, depending on the forms used.
• the dosage varies in accordance with the age and weight of the patient, the administration route, and associated treatments, and ranges from 0.5 to 25 mg of active ingredient from 1 to 3 times per day.
• the melting points were determined either using a Kofler hot plate (K), or a hot plate under a microscope (MK).
• Step C 4-Oxocyclopenta g!-3,4-dihydro-2H-benzopyran
• Step D 4-Hydroxyiminocyclopenta g!-3,4-dihydro-2H-benzopyran
• Step E 4-p-Toluenesulphonyloxyiminocyclopenta g!-3,4-dihydro-2H-benzopyran
• Step B 3-Propionylamino-4-hydroxycyclopenta g!-3,4-dihydro-2H-benzopyran
• Step D Trans-3-(N-propyl-N-chloroacetylamino)-4-hydroxycyclopenta g!-3,4-dihydro-2H-benzopyran
• Step E Trans-3,4,4a, 11b-tetrahydro-3-oxocyclopenta g!-1,4-oxazino 5,6-c!-4-propyl-5H-benzopyran
• Step F Trans-3,4,4a, 11b-tetrahy.drocyclopenta g!- 1,4-oxazino 5,6-c!-4-propyl-5H-benzopyran
• Step 4 Trans-2,3,5,6,7,8-hexahydro-8-hydroxy-7-(N-propyl-N-chloroacetylamino)-naphtho-2,3-b!thiophene
• Step 5 Trans-3,4,4a,5,6,8,9,11b-octahydrothieno 2,3 -b!-3-oxo-1,4oxazino 3,2-h!-4-propyl-2H-naphthalene
• reaction mixture is taken up in H 2 O (200 ml) and CH 2 Cl 2 (100 ml), the phases are separated, and the aqueous phase is extracted three times with CH 2 Cl 2 (50 ml each time). The organic phases are combined, washed with brine, dried over magnesium sulphate and concentrated to yield 5.86 g of the expected product in the form of a solid.
• the residue is taken up in 200 ml of methanol and heated at reflux for 1.5 hours in the presence of 1 ml of aqueous 37 % HCl, then concentrated in vacuo.
• the solid residue is taken up in 100 ml of ethyl ether and 100 ml of 1N sodium hydroxide solution.
• the aqueous phase is extracted four times with 60 ml of ethyl ether each time.
• the organic phases are combined, washed with brine, dried over magnesium sulphate and concentrated to yield 5.14 g of a thick oil. That residue is taken up in 100 ml of ethyl ether and the title product in the form of the hydrochloride (4.67 g, yield: 90 %) is precipitated by the addition of ethereal hydrogen chloride.
• More polar sulphoxide M.p.(MK): 169°-170° C.
• the affinity of the compounds of the invention for D 3 and D 2 receptors was determined on membrane preparations using 125 I!-iodosulpride as radioligand, raclopride (10 ⁇ M) determining the non-specific binding. The results are expressed as IC 50 values.
• the tests were carded out on male Wistar rats weighing 200-250 g placed in individual cages with free access to food and water. The products were dissolved in distilled water to which several drops of lactic acid are added. The injections were effected in a volume of 1.0 ml/kg by the subcutaneous route. The doses are expressed in terms of the base. The rectal temperature of the rats was recorded using a digital thermistoprobe (Millan et al, I.P.E.T., 1993, 264, p. 1364-1376). During a first period, the rats were injected with the compound to be tested or the carrier, and were then put back in their cages for 30 minutes.
• the rats were then given an injection of 7-OH-DPAT (0.16 mg/kg) and were placed in their cages again. Thirty minutes later, the rectal temperature was measured and the difference was determined by comparison with the base values (.increment.T° C.).
• the inhibitory dose (95 % confidence limits) for reducing the effect of the 7-OH-DPAT by 50 % was calculated according to the Finney method (Statistical Method in Biological Assays, 2nd ed., Hafner Publishing, New York, 1964).
• the affinities (IC 50 ) of the products of the invention for the D 3 receptor are from 10 -9 M to 10 -7 M, whilst those for the D 2 receptor are from 10-7 M to 10 -5 M.

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• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Psychiatry (AREA)
• Addiction (AREA)
• Hospice & Palliative Care (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 1995
  • 1995-11-09 FR FR9513270A patent/FR2741074B1/fr not_active Expired - Fee Related
• 1996
  • 1996-11-05 NO NO964672A patent/NO308132B1/no unknown
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  • 1996-11-07 JP JP8295025A patent/JPH09169770A/ja active Pending
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